Phosphonium compounds for treating gastrointestinal hyperacidity and ulceration

ABSTRACT

ARALKYL PHOSPHONIUM SALTS OF THIS INVENTION POSSESS USEFUL GASTIC ANTI-SECRETORY, SPASMOLYTIC AND ANTIULCEROGENIC PROPERTIES. A METHOD OF TREATING GASTROINTESTINAL HYPERACIDITY AND ULCERATION HAS ALSO BEEN DISCLOSED.

United States Patent Oflice 3,810,979 Patented May 14, 1974 US. Cl. 424-498 8 Claims ABSTRACT OF THE DISCLOSURE Aralkyl phosphonium salts of this invention possess useful gastie anti-secretory, spasmolytic and antiulcerogenic properties. A method of treating gastrointestinal hyperacidity and ulceration has also been disclosed.

This is a division, of application Ser. No. 99,313, filed Dec. 17, 1970, now Pat. No. 3,742,064.

SUMMARY OF THE INVENTION This invention describes new phosphonium salts and processes for their preparation. This invention further provides valuable pharmaceutical preparations which contain these phosphonium salts as gastic antisecretory, spasmolytic, and antiulcerogenic agents. A method for the treatment of gastrointestinal hyperacidity and ulceration is also described.

BACKGROUND OF THE INVENTION The pharmaceutical compositions which have been used as antisecretory and spasmolytic agents have been such as atropine, homatropine, propantheline bromide, dicyclomine hydrochloride and other compounds which are structurally dissimilar to the onium salts of this invention. Due to the anticholinergic properties of these known compounds, they produce undesirable side effects such as mydriasis, xerostomia, cyclopegia, and other unwanted effects.

There have been a number of aralkyl and alkyl phosphonium salts described in the literature with a lower alkyl group having up to 4 carbon atoms. They have mainly been proposed for use as bactericidal and fungicidal agents, and as plant growth regulators.

We have unexpectedly found novel phosphonium salts which have valuable pharmacologic properties.

We have found phosphonium salts which possess useful gastric antisecretory, spasmolytic, and antiulcerogenic properties.

We have further found trialkyl aralkyl phosphonium salts which are novel.

We have also found that the compounds of this invention are substantially void of the anticholinergic side elfects which accompany heretofore known gastric antisecretory and spasmolytic agents.

We have still further found a simple and effective method for treating gastric hyperacidity and gastrointestinal ulceration such as duodenal and peptic ulcers.

We have found a class of therapeutically effective compounds which can also be conveniently synthesized.

DESCRIPTION AND PREFERRED EMBODIMENTS This invention provides a method of preparing novel phosphonium salts.

This invention further provides pharmocologically active chemical compounds which are useful in treating gastrointestinal hyperacidity and ulceration.

The compounds of this invention may be described by the general Formula I:

where Aralk is an arloweralkyl or substituted arloweralkyl R is a saturated or unsaturated acyclic member having from 5 to 12 carbon atoms, or a saturated or partially saturated carbocyclic member having from 5 to 12 carbon atoms; and

X- is a nontoxic inorganic or organic anion.

More specifically, the compounds of this invention may be described by structural Formula II:

where:

R, is hydrogen, loweralkyl, loweralkenyl, cycloloweralkyl, cycloloweralkenyl, aryl (preferably phenyl, tolyl, xylyl, etc.) or arloweralkyl (preferably benzyl, etc.);

R R R R and R may be the same or different and are hydrogen, loweralkyl, halo, haloloweralkyl, nitro, amino, monoand diloweralkylamino, acylamino cyano, carbamyl, carboxy, carbloweralkoxy, loweralkoxy, haloloweralkoxy, hydroxy, acyl, haloacyl, acyloxy, phenoxy, halophenoxy, phenyl, halophenyl, thiocyanato, mercapto, loweralkylthio, loweralkylsulfinyl, loweralkylsulfonyl, haloloweralkylsulfonyl, sulfo, sulfonamido, sulfinami-do, diloweralkylsulfonamido or halodiloweralkylsulfonamido;

R is a 5 to 12 carbon atom member which may be straight chained or branched and is alkyl, alkenyl, cycloal'kenyl, cycloalkyl, cycloalkylloweralkyl, spiroalkyl, bicycloalkyl; and

X* is a pharmaceutically acceptable nontoxic organic or inorganic anion (preferably chloride, bromide, iodide, sulfate, hydrogen sulfate, nitrate, phosphate, dihydrogenphosphate, monohydrogenphosphate, acetate, maleate, citrate, benzoate, lactate, benzenesulfonate, methanesulfonate, ethanesulfonate, etc.).

The more preferred compounds of this invention are also the more preferred compounds which are useful in treating gastrointestinal disorders and iseases and are described by the structural Formula III:

R, is hydrogen or loweralkyl;

R R R R and R are hydrogen, halo, cyano, haloloweralkyl, nitro, haloloweralkoxy, haloloweracyl, haloloweralkylsulfonyl or halodiloweralkylsufonamido;

R is a 5 to 12 carbon atom member which may be straight chained or branched and is akyl, alkenyl, cycloalkenyl or cycloalkyl; and

X- is chloride, bromide, iodide, nitrate, phosphate or sulfate.

The most preferred compounds of this invention em brace those compounds of structural Formula IH where:

R is hydrogen or methyl;

R R R R and R are hydrogen, fluoro, chloro, bromo,

iodo, trifluoromethyl or nitro;

R is hexyl, heptyl, octyl, cyclohexyl, cycloheptyl or cyclooctyl; and

X- is chloride, bromide or iodide.

In the descriptive portions of this invention, the following definitions apply: The term lower alkyl refers to a lower al kyl hydrocarbon group containing from 1 to about 8 carbon atoms which may be straight chained or branched.

The term lower alkenyl refers to a lower alkenyl hydrocarbon group containing from 1 to about 8 carbon atoms which may be straight chained or branched.

The acyl radical may be any organic radical derived from an organic acid by the removal of its hydroxyl group, such as acetyl, propionyl, benzoyl, etc.

The lower alkoxy radical signifies an alkoxy group containing from 1 to about 8 carbon atoms which can be straight chained or branched.

The compounds of this invention can contain an asymmetric carbon atom when n=1 and R, is not H. For this reason, they may be obtained as racemic mixtures or as dextro and levorotatory (i isomers. These may be separated by any of the various methods of resolution to obtain the d or 1 compound. It is understood that these optical isomers are embraced within the scope of this invention.

Representative compounds of this invention which are particularly useful are as follows:

trioctylbenzyl phosphonium chloride trioctyl(o-ch1orobenzyl)phosphonium chloride trioctyl (m-chlorobenzyl phosphonium chloride trioctyl(p-chlorobenzyl)phosphonium chloride trioctyl(p-trifluoromethylbenzyl)phosphonium chloride trioctyl(p-trifiuoromethoxybenzyl)phosphonium chloride trioctyl (p-dimethylsulfamylbenzyl pho s phonium chloride trioctyl(2,3-dichlorobenzyl)phosphonium chloride trioctyl(2,5-dichlorobenzyl)phosphonium chloride trioctyl'(3,4-dichlorobenzyl)phosphonium chloride trioctyl 3 ,5 -dichlorobenzyl phosphonium chloride trioctyl(2,3,4-dichlorobenzyl) phosphonium chloride trioctyl(2,3,5-dichlorobenzyl)phosphonium chloride trioctyl(2,3,6-dichlorobenzyl)phosphonium chloride trioctyl(2,4,5-dichlorobenzyl)phosphonium chloride trioctyl(3,4,5-dichlorobenzyl)phosphonium chloride trioctyl(2,6-dichlorophenethyl)phosphonium chloride trioctyl(2,6-dibromobenzyl)phosphonium bromide trioctyl(2,4,6-trichlorobenzyl)phosphonium chloride trioctyl(2,4,6-tribromobenzyl)phosphonium bromide triocty1( 2,6-dichlorobenzyl)phosphonium chloride trioctyl(2,4-dichlorobenzyl)phosphonium chloride trioctyl(2,4-dibromobenzyl)phosphonium bromide trioctyl 2, 6-dichloro-a-methyl-benzyl phosphonium chloride trioctyl 3 ,5 -ditrifluoromethylb enzyl phosphonium chloride trioctyl'(3,4,5-trimethoxybenzyl)phosphonium chloride trioctyl(2,4,6-trimethoxybenzyl)phosphonium chloride trioctyl(3,5-dichloro-4-methoxybenzyl)phosphonium chloride trioctyl(2,3,5,6-tetrafluorobenzyl)phosphonium chloride trioctyl(2,3,4,5-tetrafluorobenzy1)phosphonium chloride trioctyl (2,6-dibromo-4-trifluoromethylbenzyl) phosphonium bromide trioctyl(2,4,6-tribromobenzyl)phosphonium bromide trioctyl(2,6-dibromo-4-chlorobenzyl)phosphonium chloride trioctyl(2,6-dichloro-4-bromobenzyl)phosphonium chloride trioctyl(2,6-dichloro-4-trifluoromethylbenzyl) phosphonium chloride trioctyl(2,4-dichloro-6-thiocyanatobenzyl)phosphonium chloride trioctyl(2,6-di'bromo-4-fiuorobenzyl)phosphonium bromide trioctyl(2,6-dichloro-4-thiocyanatobenzyl)phosphonium chloride trioctyl (2,6-dichloro-4-fiuorobenzyl phosphonium chloride trioctyl(2,6-dibromo-4-iodobenzyl)phosphonium iodide trioctyl 2,6-dichloro-4-nitrobenzyl) phosphonium chloride trioctyl 2,4-dichloro-6-nitrobenzyl phosphonium chloride trioctyl (2,6-dibromo-4-nitrobenzyl) phosphonium bromide trioctyl(2,6-dichloro-4-cyanobenzyl)phosphonium chloride trioctyl(2,6,4'-trichloro-4-dibenzy1)phosphonium chloride trioctyl 2, 6-dichloro-4-phenoxybenzyl )phosphonium chloride trioctyl (2,6,4'-trichloro-4-phenoxybenzyl phosphonium chloride trioctyl(2,6-dibromo-4-(4-chlorophenoxy)benzyl) phosphonium bromide trioctyl 2,6-dibromo-4-phenoxybenzyl phosphonium bromide trioctyl (2, 6-dibromo-4'-chloro-4-dibenzyl) phosphonium bromide triheptyl(2,6-dichlorobenzyl) phosphonium chloride triheptyl(2,6-dibromobenzyl)phosphonium bromide triheptyl(2,4,6-trichlorobenzyl)phosphonium chloride triheptyl(2,4,6-tribromobenzyl) phosphonium bromide triheptyl(2,6-dibromo-4-trifiuoromethylbenzyl) phosphonium bromide triheptyl(2,6-dibromo-4-nitrobenzyl)phosphonium bromide trinonyl(2,6-dichlorobenzyl)phosphonium chloride trinonyl (2,6-dibr0mobenzyl phosphonium bromide trihexyl(2,6-dichlorobenzyl)phosphonium chloride tricyclohexyl(2,6-dichlorobenzyl)phosphonium chloride tricycloheptyl(2,6-dichlorobenzyl)phosphonium chloride tricyclooctyl(2,6-dichlorobenzyl)phosphonium chloride trihexyl(2,4,6-trichlorobenzyl)phosphonium chloride tridecyl(2,6-dichlorobenzyl)phosphonium chloride triundecyl(2,6-dichlorobenzyl) phosphonium chloride tridodecyl(2,6-dichlorobenzyl)phosphonium chloride trioctyl(2,6-dichlorobenzyl)phosphonium bromide trioctyl( 2,6-dichlorobenzyl)phosphonium iodide trioctyl(2,6-dichlorobenzyl)phosphonium sulfate trioctyl(2,6-dichlorobenzyl)phosphonium nitrate trioctyl(2,6-dichlorobenzyl)phosphonium phosphate trioctyl(2,6-dichlorobenzyl)phosphonium acetate trioctyl(2,6-dichlorobenzyl) phosphonium benzoate The compounds of this invention may be prepared by the following general procedures:

Condensation of a trisubstituted phosphine and an aralkylhalide results in the corresponding aralkyl trisubstituted phosphonium halide.

The following reaction equation illustrates this synthesis:

Re. /R

in n R R5 Re R Ra Ra: /R R. -(d -i -R xia. n R 5 R! where n, R, R 'R R R R and R are as described above and X" is halogen.

The reaction is preferably carried out on the aralkyl bromide or chloride using a solvent and with increased temperatures.

The reaction is preferably carried out in an inert atmosphere preferably nitrogen or carbon dioxide. The solvent should be one that is miscible with the reactants and is convenient to use the reactant halide in excess as the solvent or alternatively a high boiling polar medium such as phenol, acetonitrile, dimethylformamide, dimethylsulfoxide, methylethylketone, isopropanol, 2 nitropropane, etc. The reaction temperature may vary from room temperature with readily reactive reactants to about 250 0., although it is preferable to run the reaction at temperatures from about 50 C. to 150 C. The isolation of the desired phosphonium halide can be carried out by distilling oh? the solvent in vacuo and precipitating the phosphonium halide by the addition of a hydrocarbon liquid such as n-pentane, n-hexane, cyclohexane, etc. Other anions can be produced by exchange of the halide with alkali or alkaline earth salts containing the appropriate anion.

The starting materials employed in these foregoing methods are either known compounds or they may be prepared by the following reaction sequences.

The benzyl and phenethyl halide starting materials can be conveniently prepared by the following reactions:

Rs R R: 2

t r B6 l... 1.16 Re 1'...

where n R R R R R and R are as described above.

The reaction is normally carried out by treating a benzene solution of a benzyl or phenethyl alcohol with phosphorous trihalide, phosphorous oxyhalide, phosphorous pentahalide, thiomylhalide or sulfuryl halide at reflux temperature for about one hour. This can also be performed in other inert solvents (such as toluene, chloroform, carbon tetrachloride, etc.) or by using excess halogenating agent as solvent. A temperature from about 50 to 150 C. is satisfactory. The benzyl alcohols may be prepared by the following reaction sequence.

R: R: R:

Ra Ra Ra. niwon R (211-011 it. Ra Ra Ra a Diazotization of an aromatic amine in the conventional manner followed by a Sandmeyer (a) type displacement produces the nitrile, which is then hydrolyzed (b) to the carboxylic acid. Rosenmund reduction (0) of the carboxylic acid results in the aldehyde which in turn is interacted with the desired Grignard reagent and oxidized (d) to obtain the a-ketone. This may then either be reduced catalytically (e) to the lat-substituted benzyl alcohol or a second Grignard reaction (f) may be carried out to obtain the a,a-disubstituted benzyl alcohol. Lithium aluminum hydride reduction of the benzoic acid (g) results in the benzyl alcohol.

The phenethylhalide starting materials may be prepared in an analogous manner starting with the substituted a-phenylalkanoic acid.

Lithium aluminumhydride reduction (v) of the proper phenylacetic acid results in the corresponding phenylethanol. This alcohol may also be prepared by catalytically reducing (w) the desired phenylacetaldehydc. A Grignard reaction (x) on the latter compound results in the a-Substituted ketone which may then either be reduced catalytically (y) to the var-substituted phenethanol or a second Grignard reaction (2) may be carried out to obtain the a,u-disubstituted phenethanol.

Appropriately desired end products having various R R R R and R substituents can. be prepared at various stages of the synthesis of the starting materials by using suitable reactions in order to convert one group to another. Thus, for example, using conventional methods, a halogen group can be treated under Rosenmund Von Brown conditions to the nitrile compound which in turn can be hydrolyzed to a carboxy. A nitro can be reduced to an amino which can be alkylated to the dialkylamino substituent. A 'hydroxy compound can be prepared by demethylation of a methoxy substituent. A Sandmeyer type reaction can be carried out on an amino compound to introduce a chloro, bromo, xanthate, hydroxyl or alkoxyl group. The xanthate can then lead to the mercapto by hydrolysis, this in turn can be alkylated to a alkylthio group which can be oxidized to alkylsulfinyl and alkylsulfonyl groups. A thiocyanato group may be reduced to a mercapto. An iodo group may be removed by catalytic hydrogenation.

Tertiary phosphines having the same groups may be prepared from phosphorous halides with organometallic compounds by procedures known in the art.

where R is as described above and X is halide.

For the preparation of tertiary phosphines with unlike groups, phosphor halo compounds may be reacted with an organometallic compound as above. These may be obtained by alkali cleavage of phosphonium salts according to conventional methods in the art. Thus, for example, with the correct choice of starting materials tertiary phosphines with three or, after quaternization, phosphonium salts with four different ligands can be prepared.

We have found that the compounds of this invention have useful antiulcerogenic properties. Further, they have an effective degree of gastric antisecretory activity, i.e., they reduce the volume and the acidity of the gastric fluid in humans and mammals. Still further, these compounds produce a considerable spasmolytic action on the gastrointestinal musculature, i.e., they reduce the peristaltic action of the gastrointestinal musculature which is manifested by a delay in gastric emptying time.

Until now, the known anti-ulcerogenic compounds which showed gastric antisecretory and gastrointestinal spasmolytic action have included such agents as atropine, homatropine, propantheline, dicyclomine, etc. These compounds, however, cause accompanying undesirable anticholinergic properties such as mydriasis, xerostomia, cyclopegia, etc.

We have found that the phosphonium compounds of this invention are particularly useful as anti-secretory, anti-spasmodic and antiulcerogenic agents because they are essentially devoid of these unwanted effects.

In particular, the phosphonium compounds, as herein described are useful in the treatment of such gastrointestinal disorders and diseases as duodenal ulcer and peptic lucer. v

For all these purposes, the phosphonium compounds of this invention can be administered orally or parenterally, but they are preferably administered orally. Orally, they may be administered as tablets, aqueous or oily suspensons, dispersizble powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. The term parenteral, as used herein, includes subcutaneous injection, intramuscular injection or infusion techniques.

Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a pharmaceutically elegant and palatable preparation.

Further, these compounds may be tableted or otherwise formulated so that for every 100 parts by weight of the composition, there are present between and 95 parts by weight of the active ingredient. The dosage unit form will generally contain between about 1 mg. and about 500 mg. of the active ingredients of this invention. The preferred unit dose is between about 10 mg. and 100 mg.

The dosage regimen in carrying out the methods of this invention is that which insures maximum therapeutic response until improvement is obtained and thereafter the minimum effective level which gives relief. Thus, in general, the dosages are those that are therapeutically effective in the treatment of ulcerogenic disease conditions or symptoms, such as duodenal and peptic ulcer. In general, the (daily dose can be between about 0.1 mg./kg. and 50 mg./kg. (preferably in the range of 1-25 mg./kg./day). Bearing in mind, of course, that in selecting the appropriate dosage in any specific case, consideration must be given to the patients weight, general health, age and other factors which may influence response to the drug.

Various tests in animals have been carried out to show the ability of the compounds of this invention to exhibit reactions that can be correlated with antiulcerogenic activity in humans. These tests involve such as the effect of the phosphonium compounds on gastric secretion, gastrointestinal spasm and their effect against ulcerogenic agents. It has been found that the compounds of this invention when tested in the above variety of situations show a marked activity.

One such test is the gastric secretion test. This test is carried out as follows: Shay rats are fasted for 4-8 hours, and water is given ad lib. The rats are selected at random and separated into groups of 10. The animals are treated intraduodenally (I.D.) with the test compound or the vehicle immediately subsequent to the ligation of the stomach at the pyloric sphincter. The animals are sacrificed with chloroform at 4 hours post-drug administration, the stomach is removed and its contents are are assayed for volume, pH and total acids.

A second gastric secretion test is carried out on dogs. This is outlined in the Handbook of Physiology, Section 6: Alimentary Canal, Volume II: Secretion, American Physiology Society, Washington, D.C., 1967.

It has been found that the compounds of this invention when subjected to the above gastric secretion tests display a marked ability to decrease gastric volume and gastric acidity. These tests are known to correlate well with gastric activity in humans and is a standard test used to determine anti-secretory properties.

To determine the anti-ulcer effectiveness, the following test is employed: Male Wistar rats (130l50 grams) are fasted for 24 hours, then given reserpine at 5 mg/kg. i.p. Twenty-four hours later, the stomachs are removed and examined for ulceration. Ulcers are graded on a 0-4 scale and the number of ulcers is recorded. Pretreatment with the phosphonium compounds of this invention produces a decrease in ulcer grade and the number of ulcers compared to the control reserpine-treated rats.

Determination of anti-spasmodic properties can be carried out by the procedure as outlined by D. A. Brodie and S. K. Kundrats in their article entitled Effect of Drugs on Gastric Emptying in Rats, Fed. Proc. 24:714 (1965).

Mydriasis is detected by the procedure R. A. Turner, Screening Methods in Pharmacology, Academic Press, New York, and London, pp. 174-5, 1965. Acute toxicity is calculated according to the standard Litchfield- Wilcoxon procedure.

In view of the results of these tests, the pharmacological data clearly indicates that the phosphonium compounds of this invention can be considered to be effective antiulcerogenic, antisecretory, and antispasmodic agents which are substantially free of anticholinergic side effects and having a low toxicity.

The following are detailed examples which show the preparation of the compounds of this invention. They are to be construed as illustrations of said compounds and not as limitations thereof.

EXAMPLE 1 Tri-n-heptyl phosphine To a 'Grignard mixture of n-heptylmagnesium chloride (0.43 mole) prepared from (10.9 g. of magnesium tumings and 57.5 g. of n-heptyl chloride) is added 13.2 g. (0.096 mole) of phosphorous trichloride in ml. of ether, in a nitrogen atmosphere, and 0 C. The reaction mixture is allowed to warm to room temperature with stirring over 2 hours. This is then poured onto an ice-cold saturated solution of ammonium chloride (250 ml.) and the mixture stirred for one hour. The aqueous layer is extracted with 200 ml. of ether, dried over sodium sulfate, evaporated to dryness and distilled to give tri-n-heptyl phosphine (B.P. 144/0.1 mm.).

When n-heptyl chloride in the above reaction is substituted with the halide of Table I below, then the corresponding product of Table 11 below is prepared.

TABLE I n-Pentyl chloride n-Hexyl chloride n-Octyl chloride n-Nonyl chloride n-Decyl chloride n-Undecyl chloride n-Dodecyl chloride Isoamyl chloride Z-methyl-l-butenyl chloride Cyclohex-Z-enyl chloride Cyclohex-3-enyl chloride Cycloheptyl chloride Cyclopentyl chloride Cyclohexyl chloride Cyclohexylmethyl chloride 3,5,5-trimethylheptyl chloride 2-propylallyl chloride 4-methyl-3-penten-l-yl chloride Z-methylheptyl chloride 3-methylheptyl chloride 2-ethylhexyl chloride 2,2,3,3-tetramethylbutyl chloride Cyclooctyl chloride Cyclooct-Z-enyl chloride Bicyclo(3.2.1 )oct-2-yl chloride Iso-octenyl chloride Spiro(3 .4)oct-2-yl chloride TABLE II Tri-n-pentyl phosphine Tri-n-hexyl phosphine Tri-n-octyl phosphine Tri-n-nonyl phosphine Tri-n-decyl phosphine Tri-n-undecyl phosphine Tri-n-dodecyl phosphine Tri-isoamyl phosphine Tris- (Z-methyll-butenyl phosphine Tris- (cyclohex-Z-enyl phosphine Tris-(cyclohex-B-enyl)phosphine Tricycloheptyl phosphine Tricyclopentyl phosphine Tricyclohexyl phosphine Tricyclohexylmethyl phosphine Tris- 3,5,5-trimethylheptyl phosphine Tris-(2-propylallyl)phosphine Tris-(4-methyl-3-penten-1-yl)phosphine Tris-(Z-methylheptyl)phosphine Tris-(3-methy1heptyl)phosphine Tris-(2-ethylhexyl)phosphine Tris-(2,2,3,3-tetramethylbutyl)phosphine Tricyclooctyl phosphine Tris-(cyclooct-Z-enyl)phosphine Trisbicyclo [3 .2. 1 oct-2-yl) phosphine Tri-(iso-octenyl)phosphine Tri-(spiro[3.4]oct-2-yl)phosphine When phosphorous trichloride in the above example is replaced with dichloroheptylphosphine, dichlorocyclohexylphosphine and chlorodiheptylphosphine, then the starting materials prepared are dioctylheptylphosphine, dioctylcyclohexylphosphine and diheptyloctylphosphine.

EXAMPLE 2 Triocty1(p-chlorobenzyl) phosphonium chloride To 25 g. (0.0675 mole) of tri-n-octyl phosphine dissolved in 150 ml. of acetonitrile in a nitrogen atmosphere is added 11.9 g. (0.074 mole) of u,p-dichlorotoluene dissolved in 50 ml. of acetonitrile. To the mixture is added 20 ml. of benzene to cause solution. The mixture is then heated at reflux temperature for 25 hours, cooled to room temperature and evaporated in vacuo. The crude product is triturated with hexane, filtered, washed with hexane, and dried to obtain trioctyl(p-chlorobenzyl)phosphonium chloride (M.P. 75.5-78 C.).

EXAMPLE 3 Trioctyl (2,6-dichlorobenzyl )pho sphonium chloride To 91 g. (0.245 mole) of tri-n-octyl phosphine in 500 ml. of acetonitrile are added 52.8 g. (0.27 mole) of 2,6

10 dichlorobenzyl chloride. The mixture is then refluxed for 15 hours, concentrated in vacuo and the residue agitated with 3-200 ml. portions of hexane. The hexane is evaporated to give trioctyl(2,6-dichlorobenzyl)phosphonium chloride (M.P. 42-445 C.).

When tri-n-octyl phosphine in the above example is substituted for the phosphines of Example 1, then the corresponding product below is prepared.

Tri-n-pentyl(2,6-dichlorobenzyl)phosphoniurn chloride Tri-n-hexyl(2,6-dichlorobenzyl)phosphonium chloride Tri-n-heptyl 2, 6-dichlorob enzyl phosphonium chloride Tri-n-nonyl( 2, 6-dichlorobenzyl phosphonium chloride Tri-n-decyl (2,6-dichlorob enzyl) phosphonium chloride Tri-n-undecyl(2,6-dichlorobenzyl)phosphonium chloride Tri-n-dodecyl 2, 6- dichlorobenzyl) phosphonium chloride Tri-isoamyl(2,6-dichlorobenzyl)phosphonium chloride Tris- Z-methyll-butenyl) (2,6-dichlorobenzyl) phosphonium chloride Tris- (cyclohex-Z-enyl) (2,6-dichlorobenzyl) phosphonium chloride Tris-(cyclohex-3-enyl) (2,6-dichlorobenzyl)phosphonium chloride Tricycloheptyl(2,6-dichlorobenzyl)phosphonium chloride Tricyclopentyl(2,6-dichlorobenzyl)phosphonium chloride Tricyclohexyl(2,6-dichlorobenzyl)phosphonium chloride Tricyclohexylmethyl(2,6-dichlorobenzyl)phosphonium chloride Tris- 3,5 ,5 -trimethylheptyl) (2,6-dichlorobenzyl) phosphonium chloride Tris- (Z-propylallyl) (2,6-dichlorobenzyl)phosphonium chloride Tris-(4-methyl-3-penten-1-yl) (2,6-dichlorobenzyl) phosphonium chloride Tris- Z-methylheptyl) (2,6-dichlorobenzyl) phosphonium chloride Tris- 3 -methylheptyl) (2,6-dichlorobenzyl phosphonium chloride Tris- Z-ethylhexyl) (2,6-dichlorobenzyl) pho sphonium chloride Tris-(2,2,3,3-tetramethylbutyl) (2,6-dichlorobenzyl) phosphonium chloride Tricyclooctyl(2,fi-dichlorobenzyl)phosphonium chloride Tris- (cyclooct-Z-enyl) (2,6-dichlorobenzyl) phosphonium chloride Tris- (bicyclo[ 3 .2. 1 oct-2-yl) (2,6-dichlorobenzyl) phosphonium chloride Tri-(isooctenyl) (2,fi-dichlorobenzyl)phosphonium chloride Tri-(spiro [3.4]oct-2-yl) (2,6-dichlorobenzyl) phosphonium chloride Dioctylheptyl 2,6-dichlorobenzyl) phosphonium chloride Dioctylcycloheptyl(2,6-dichlorobenzyl)phosphonium chloride Diheptyloctyl(2,6-dichlorobenzyl)phosphonium chloride.

EXAMPLE 4 Trioctyl(2,6-dichlorobenzyl)phosphonium bromide 48 g. of trioctyl(2,6-dichlorobenzyl)phosphonium chloride is added to 200 ml. of a saturated aqueous sodium bromide solution. The mixture is then heated to the solid is melted and the mixture is stirred for 5 min., cooled in an ice-bath and the water decanted. Another 200 ml. of saturated sodium bromide solution is added and the procedure repeated. The ion exchanged phosphonium bromide is filtered, washed with 1 liter of water followed by 2-200 ml. portions of hexane. The product is then heated twice with 300 ml. of distilled Water until a melt, cooled and the water decanted, triturated with hexane,

11 and dried to obtain trioctyl(2,6-dichlorobenzyl)phosphonium bromide (M.P. 86-875 C.).

When the sodium bromide solution of the above example is replaced with a solution of an appropriate salt of Table 1 below, then the corresponding desired phosphonium salt of Table II below is obtained.

TABLE I Potassium oxalate Potassium bromide Sodium phosphate Lithium bromide Sodium benzoate Sodium methanesulfonate.

TABLE II Sodium iodide Sodium sulfate Sodium nitrate Sodium maleate Sodium citrate Sodium acetate EXAMPLE 5 Trioctyl (p trifluoromethylbenzyl) phosphonium chloride To 14.8 g. (0.04 mole) of tri-n-octyl phosphine suspended in 100 ml. of acetonitrile is added 9.7 g. (0.05 mole) of p-trifluoromethylbenzyl chloride in 75 ml. of acetonitrile. The reaction mixture is then heated at reflux for 24 hours, cooled and evaporated to dryness in vacuo. The residue is dissolved in hexanezether, treated with charcoal, filtered and concentrated to dryness in vacuo to obtain trioctyl(p-trifluoromethylbenzyl) phosphonium chloride.

When the starting materials of Table -1 below are used in place of p-trifluoromethylbenzyl chloride in the above example, then the corresponding product of Table II below is obtained.

TABLE I Benzyl bromide Benzyl chloride Benzyl iodide p-Trifiuoromethoxybenzyl chloride p-Trifiuoroacetylbenzyl chloride o-Trifluoromethylbenzyl chloride p-Trifluoromethylsulfonylbenzyl chloride 3,5-dimethy1benzyl bromide o-Chlorobenzyl chloride m-Chlorobenzyl chloride p-Chlorobenzyl chloride p-Ditrifluoromethylsulfamylbenzyl chloride p-Dimethylsulfamylbenzyl chloride p-Bromobenzyl bromide 2,6-dichloro-4-thiocyanatobenzyl chloride 2,4-dichlorobenzyl chloride 2,3-dichlorobenzyl chloride 3,4-dichlorobenzyl chloride 3,5-dichlorobenzyl chloride 2,5-dichlorobenzyl chloride m-Nitrobenzyl chloride p-Nitrobenzyl chloride p-Dimethylaminobenzyl chloride o-Methylbenzyl chloride m-Methylbenzyl chloride p-Methylbenzyl chloride p-Cyanobenzyl chloride p-Methoxybenzyl chloride p-Hydroxybenzyl chloride p-Carbethoxybenzyl chloride o-Methoxybenzyl chloride p-Acetoxybenzyl chloride p-Phenoxybenzyl chloride p- 4-chlorophenoxy) benzyl chloride p-Methylthiobenzyl chloride p-Dimethylsulfonamidobenzyl chloride a-Cyclopropylmethylbenzyl chloride a-Ethylbenzyl chloride u-Allylbenzyl chloride Benzhydryl chloride a-Benzylphenethyl chloride 2,6-dibromobenzyl bromide 2,6-difluorobenzyl bromide 3,4,5-trimethoxybenzyl chloride 2,4,6-trimethoxybenzyl chloride 3,5-dichlorobenzyl chloride 2,4,6-trichlorobenzyl chloride 2,3,4-trichlorobenzyl chloride 3,4,5-trichlorobenzyl chloride 2,4,5-trichlorobenzyl chloride 2,3,S-trichlorobenzyl chloride 2,3,6-trichlorobenzyl chloride 2,4-dibromobenzyl bromide 2,4-difluorobenzyl bromide 2,4-dibromobenzyl bromide 2-bromo-4-nitrobenzyl bromide 2,3,4-trimethylbenzyl chloride 2,4,6-tribromobenzyl bromide 3,5-dibromobenzyl bromide 3,5-difluorobenzyl bromide p-(4-chlorophenyl)benzyl chloride 2,6-dichloro-4-triiluoromethylbenzyl chloride 2,5-dinitrobenzyl chloride 2,6-dichloro-4-cyanobenzyl chloride 2,6-dichloro-4-thiocyanatobenzyl chloride 2,6-dichlor0-4fluorobenzyl chloride p-Acetamidobenzyl chloride 2-methoxy-4-chlorobenzyl chloride 2,3,4,5,6-pentafluorobenzyl chloride 2,3,5,6-tetrafiuorobenzyl chloride p-Phenylbenzyl chloride 2,4-dichloro-o-thiocyanatobenzyl chloride 2,4-dichloro-6-nitrobenzyl chloride 2-nitro-4-trifluoromethylbenzyl chloride 2,6-dichloro-4-bromobenzyl bromide 3,S-ditrifluoromethylbenzyl chloride 3,5-dichloro-4-methoxybenzyl chloride 2-chloro-4-trifiuoromethylbenzyl chloride 2,6-dibromo-4-chlorobenzyl bromide 2-chloro-4-bromobenzyl chloride 2,6-dibromo-4-nitrobenzyl bromide 2,6-dichloro-4-nitrobenzyl chloride 2,6-dibromo-4-iodobenzyl iodide 2,6-dibromo-4-trifluoromethylbenzyl bromide 2,6-dibromo-4-fluorobenzyl bromide 2,6-dichloro-a-methylbenzyl chloride 2,6-dichloro-a,a-dimethylbenzyl chloride 2,6-dichloro-u-phenylbenzyl chloride 2,6-dichloro-a-cyclohexylbenzyl chloride Phenethyl chloride p-Chlorophenethyl chloride a-(Cyclohex-Z-enyl)benzyl chloride a-Tolylbenzyl chloride aXylylbenzyl chloride a-Benzylbenzyl chloride 2,6-dichlorophenethyl chloride p-Chloro-a-methylphenethyl chloride a,;3-Di-methylphenethyl chloride fl-Phenylphenethyl chloride 2,6,4'-trichloro-4-dibenzyl chloride 2,6-dichloro-4-phenoxybenzyl chloride 2,6,4'-trichloro-4-phenoxybenzyl chloride 2,6-dibromo-4-(4-chlorophenoxy)benzyl bromide 2,6-dibromo-4-phenoxybenzyl bromide 2,6-dibromo-4'-chloro-4-dibenzyl bromide.

13 TABLE II Trioctylbenzyl phosphonium bromide Trioctylbenzyl phosphonium chloride Trioctylbenzyl phosphonium iodide Trioctyl(p-trifluoromethoxybenzyl)phosphonium chloride Trioctyl(p-trifiuoroacetylbenzyl)phosphonium chloride Trioctyl(o-trifluoromethylbenzyl)phosphonium chloride Trioctyl (p-trifiuoromethylsulfonylbenzyl phosphonium chloride Trioctyl (p-dimethylsulfamylbenzyl) phosphonium chloride Trioctyl(3,5-dimethylbenzyl)phosphonium bromide Trioctyl(o-chlorobenzyl)phosphonium chloride Trioctyl(m-chlorobenzyl)phosphonium chloride Trioctyl (p-chlorobenzyl)phosphonium chloride Trioctyl(p-di-trifluoromethylsulfamylbenzyl) phosphonium chloride Trioctyl(p-bromobenzyl)phosphonium bromide Trioctyl(2,6-dichloro-4-thiocyanatobenzyl)phosphonium chloride Trioctyl(2,4-dichlorobenzyl)phosphonium chloride Trioctyl(2,3-dichlorobenzyl)phosphonium chloride Trioctyl(3,4-dichlorobenzyl)phosphonium chloride Trioctyl(3,5-dichlorobenzyl)phosphonium chloride Trioctyl(2,S-dichlorobenzyl)phosphonium chloride Trioctyl(m-nitrobenzyl)phosphonium chloride Trioctyl(p-nitrobenzyl)phosphonium chloride Trioctyl (p-dimethylaminobenzyl phosphonium chloride Trioctyl(o-methylbenzyl)phosphonium chloride Trioctyl(m-methylbenzyl)phosphonium chloride Trioctyl(p-methylbenzyl)phosphonium chloride Trioctyl(p-cyanobenzyl)phosphonium chloride Trioctyl(p-methoxybenzyl)phosphonium chloride Trioctyl(p-hydroxybenzyl)phosphonium chloride Trioctyl(p-carbethoxybenzyl)phosphonium chloride Trioctyl(o-methoxybenzyl)phosphonium chloride Trioctyl(p-acetoxybenzyl)phosphonium chloride T rioctyl(p-phenoxybenzyl) phosphonium chloride Trioctyl [p- (4-chlorophenoxy) benzyl] phosphonium chloride Trioctyl(p-methylthiobenzyl)phosphonium chloride Trioctyl(p-dimethylsulfonamidobenzyl)phosphonium chloride Trioctyl a-cyclopropylmethylb enzyl) pho sphonium chloride Trioctyl(a-ethylbenzyl)phosphoniurn chloride Trioctyl(u-allylbenzyl)phosphonium chloride Trioctyl(benzhydryl)phosphonium chloride Trioctyl(a-benzylphenethyl)phosphonium chloride Trioctyl(2,6-dibromobenzyl)phosphonium bromide Trioctyl(2,6-difiuorobenzyl)phosphonium bromide Trioctyl(2,4-dibromobenzyl)phosphonium bromide Trioctyl(3,4,5-trimethoxybenzyl)phosphonium chloride Trioctyl(2,4,6-trimethoxybenzyl)phosphonium chloride Trioctyl(3,5-dichlorobenzyl)phosphonium chloride Trioctyl(2,4,6-trichlorobenzyl)phosphonium chloride Trioctyl(2,3,4-trichlorobenzyl)phosphonium chloride Trioctyl(3,4,5-trichlorobenzyl)phosphonium chloride Trioctyl(2,4,5-trichlorobenzyl)phosphonium chloride Trioctyl (2,3,5 -trichlorobenzyl) phosphonium chloride Trioctyl 2,3,6-trichlorobenzyl phosphonium chloride Trioctyl 2,4-dibromobenzyl phosphonium bromide Trioctyl(2,4-difluorobenzyl)phosphonium bromide Trioctyl(2-bromo-4-nitrobenzyl)phosphonium bromide Trioctyl(2,3,4-trimethylbenzyl)phosphonium chloride Trioctyl(2,4,6-tribromobenzyl)phosphonium bromide Triocty1(3,5-dibromobenzyl)phosphonium bromide Trioctyl 3 ,5 -difiuorobenzyl phosphonium bromide T rioctyl p- (4-chlorophenyl benzyl] phosphonium chloride Trioctyl (2, G-dichloro-4-trifluoromethylbenzyl) phosphonium chloride Trioctyl(2,5 dinitrobenzyl)phosphonium chloride Trioctyl (2,6'dichloro-4-cyanobenzyl) phosphonium chloride Trioctyl 2,6-diehloro-4-thiocyanatobenzyl) phosphonium chloride Trioctyl (2,6-dichloro-4-fluorobenzyl) phosphonium chloride Trioctyl(p-acetamidobenzyl)phosphonium chloride Trioctyl 2-methoxy-4-chlorobenzyl) phosphonium chloride Trioctyl 2,3,4,5,6-pentafluorobenzyl) phosphonium chloride Trioctyl(2,3,5,6-tetrafluorobenzyl)phosphonium chloride Trioctyl(p-phenylbenzyl)phosphonium chloride Trioctyl (2,4-dichloro-6-thiocyanatobenzyl) pho sphonium chloride Trioctyl(2,4-dichloro-6-nitrobenzyll) phosphonium chloride Trioctyl Z-nitro-4-trifluoromethylbenzyl) phosphonium chloride Trioctyl 2,6-dichloro-4-bromobenzyl) phosphonium bromide Trio ctyl 3 ,5 -ditrifl'uoromethylbenzyl) phosphonium chloride Trio ctyl (3 5-dichloro-4-methoxyb enzyl) phosphonium chloride Trioctyl (2-chloro-4-trifluoromethylbenzyl) phosphonium chloride Trioctyl (2,6-dibromo-4-chlorobenzyl) phosphonium bromide Trioctyl (2-chloro-4-bromobenzyl) phosphonium chloride Trioctyl (2,6-dibromo-4-nitrobenzyl)) phosphonium bromide Trioctyl 2,6-dichloro-4-nitrobenzyl) phosphonium chloride Trioctyl 2,6-dibromo-4-iodobenzyl) phosphonium iodide Trioctyl 2,6-dibromo-4-trifluoromethylbenzyl) phosphonium bromide Trioctyl (2,6-dibromo-4-fluorobenzyl phosphonium bromide Trioctyl (2, 6-dichloro-a-methylbenzyl pho sphonium chloride Trioctyl (2, fi-dichloro-a,u-dimethylbenzyl) phosphonium chloride Trio ctyl 2, 6 -dichloro-u-phenylbenzyl) phosphonium chloride Trioctyl 2,6 -dichloro-u-cyclohexylbenzyl pho sphonium chloride Trioctyl(phenethyl)phosphonium chloride Trioctyl p-chlorophenethyl pho sphonium chloride Trioctyl [a- (cyclohex-Z-enyl) benzyl] phosphonium chloride Trioctyl(a-toly1benzyl) phosphonium chloride Tr1octyl(a-xylylbenzyl) phosphonium chloride TrioctylM-benzylbenzyl phosphonium chloride Trioctyl(2,6-dichlorophenethyl)phosphonium chloride Trioctyl (p-chloro-a methylphenethyl) phosphonium chloride Trioctyl a,/3-di-methylphenethyl) phosphonium chloride Trioctyl (,B-phenylphenethyl) phosphonium chloride Trioctyl( 2,6,4'-trichloro-4-dibenzyl)lphosphonium chloride Trioctyl 2,6-dichloro-4-phenoxybenzyl) phosphonium chloride Trioctyl (2, 6,4'-trichloro-4-phenoxybenzyl phosphonium chloride Trioctyl [2,6-dibromo-4- (4'-chlorophenoxy) benzyl] phosphonium bromide Trioctyl 2,6-dibromo-4-phenoxybenzyl) phosphonium bromide Trioctyl(2,6-dibromo-4'-chloro-4-dibenzy1)phosphonium chloride.

EXAMPLE 6 When the procedures of Examples 1-5 are followed but the starting materials are selected from Table I,

15 Example 3 and Table I, Example 5, then the following representative compounds are prepared.

Tri-n-heptyl (p-trifiuoromethylbenzyl phosphonium chloride Tri-n-hexy(2,4-dichlorobenzyl)phosphonium chloride Tricyclohexyl (p-chlorobenzyl phosphonium chloride Tricyclooctyl (p-nitrobenzyl phosphonium chloride Tricyclohexyl(p-dimethylaminobenzyl)phosphonium chloride Tri-n-nonyl(p-cyanobenzyl)phosphonium chloride Tris-(2-ethylhexyl) (3,4,5-trichlrobenzyl) phosphonium chloride Tris-(S-methylheptyl) (2,6-dibr0mobenzyl) phosphonium bromide Tricyclopentyl 2,6-dichlor0-o-methylbenzyl phosphonium chloride Tri-n-heptyl(2,3-dichlorobenzyl)phosphonium chloride Tri-n-heptyl(2,4-dichlorobenzyl)phosphonium chloride Tri-n-heptyl(2,5-dichlorobenzyl)phosphonium chloride Tri-n-heptyl( 3 ,4-dichlorobenzyl phosphonium chloride Tri-n-heptyl 2, 3,4,5 ,6-p entafluorobenzyl phosphonium chloride Tricyclohexyl(p-nitrobenzyl)phosphonium chloride Tris-(3,5,5-trimethylheptyl)benzyl phosphonium chloride Tri-n-dodecylphenethyl phosphonium chloride Tri-n-heptyl [p-(4-chlorophenyl)benzyl1phosphonium chloride Tri-(iso-octenyl) (fi-phenylphenethyl) phosphonium chloride Tri-n-pentyl(2,3,5-trichlorobenzyl)phosphonium chloride Tridodecyl(p-chlorobenzyl)phosphonium chloride Tris-(2,2,3,B-tetramethylbutyl)benzyl phosphonium chloride Tri-n-heptyl p- (4-chlorophenoxy) benzyl] phosphonium chloride Tri-n-heptyl 2,6-dibromobenzyl phosphonium bromide Tri-n-hexyl(2,6-dibromobenzyl)phosphonium bromide Tris- (Z-methylheptyl) (2,6-dibromobenzyl phosphonium bromide Tris-(2-methylheptyl) (p-trifiuoromethylbenzyl)phosphonium chloride Triscyclooct-Z-enyl) (p-trifiuoromethylbenzyl phosphonium chloride Tri-isoamyl(p-trifluoromethylbenzyl)phosphonium chloride Tris- 2-methy1- l-butenyl) (p-trifluoromethylb enzyl) phosphonium chloride Tri-n-hexyl p-trifluoromethylbenzyl phosphonium chloride Tris-(spirol [3 .4] oct-2-yl) (p-trifluoromethylbenzyl) phosphonium chloride Tri-n-heptyl(p-phenoxybenzyl)phosphonium chloride Tri-n-undecyl(2,6-dibromobenzyl)phosphonium bromide Tris-(bicyclo[3.2.1]oct-2-yl) (p-trifluoromethylbenzyl) phosphonium chloride Tri-n-heptyl( 3 ,4,5-trimethoxybenzyl) phosphonium chloride Tris-(Z-propylallyl) (p-chlorobenzyl)phosphonium chloride Triheptyl (2,4,6-tribomobenzyl phosphonium bromide Triheptyl(2,6-dibromo-4-trifluoromethylbenzyl)phosphonium bromide Triheptyl (2,6-dibromo-4-nitrobenzyl) phosphonium bromide Trinonyl(2,6-dibromobenzyl)phosphonium bromide TriheXyl(2,4,6-trichlorobenzyl)phosphonium chloride Tricyclohexyl 2,6-dibromobenzyl phosphonium bromide Tricyclohexyl(p-chlorobenzyl)phosphonium chloride.

We claim:

1. A method of treating gastrointestinal hyperacidity or ulceration in a human or mammal which comprises the oral or parenteral administration thereto of a therapeutically eifective amount of at least one compound of the formula:

| l R.x R4@- & d maxl l. Ra Re where:

n is 1-2;

R, is hydrogen, methyl, ethyl, cyclohexyl, phenyl, tolyl,

xylyl or benzyl;

R R R R and R may be the same or different and are hydrogen, methyl, chloro, bromo, fluoro, iodo, trifluoromethyl, nitro, phenyl or p-chlorophenyl;

R is pentyl, hexyl, heptyl, nonyl, decyl, undecyl,

dodeeyl, isoamyl, 3,5,5 trimethylheptyl, Z-methylheptyl, B-methylheptyl, 2 ethylhexyl, 2,2,3,3-tetramethylbutyl, isooctenyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexylmethyl, spiro [3.4] oct-2-yl or bicyclo [3.2.1] oct-Z-yl;

X- is pharmaceutically acceptable non-toxic organic or inorganic anion selected from the group consisting of chloride, bromide, iodide, sulfate, hydrogen sulfate, nitrate, phosphate, dihydrogenphosphate, monohydrogenphosphate, acetate, maleate, citrate, benzoate, lactate, benzenesulfonate, methanesulfonate and ethanesulfonate.

2. The method of claim 1 wherein the compound is of the formula:

Rs R2 where:

'R, is hydrogen or methyl,

R R R R and R are hydrogen, chloro, bromo,

fluoro, iodo, trifiuoromethyl or nitro;

R is pentyl, hexyl, heptyl, nonyl, decyl, undecyl,

dodecyl, isoamyl, 3,5,5-trimethylheptyl, Z-methylheptyl, 3-methylheptyl, Z-ethylhexyl, 2,2,3,3 tetramethylbutyl, isooctenyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; and

X- is chloride, bromide, iodide, nitrate, phosphate 0r sulfate.

3. The method of claim 2 where:

R, is hydrogen or methyl;

R R R R and R are hydrogen, fiuoro, chloro,

bromo, iodo, trifluoromethyl or nitro;

R is hexyl, heptyl, octyl, cyclohexyl, cycloheptyl or cyclooctyl; and

X- is chloride, bromide or iodide.

4. The method of claim 3 wherein the compound is trioctyl (2,6-dichlorobenzyl)phosphonium chloride.

5. The method of claim 3 wherein the compound is trioctyl (2,4,6-trichlorobenzyl)phosphonium chloride.

6. The method of claim 3 wherein the compound is trioctyl (2,6-dibromobenzyl)phosphonium bromide.

7. The method of claim 3 wherein the compound is trioctyl (2,4,6-tribromobenzyl)phosphonium bromide.

8. The method of claim 3 wherein the compound is trioctyl (p-trifiuoromethylbenzyl) phosphonium chloride.

References Cited UNITED STATES PATENTS 2,946,824 7/1960 Chiddix et al 260606.5 3,281,365 10/1966 Moedritzer 252l07 3,642,989 2/1972. Martin et al. 42421l ALBERT T. MEYERS, Primary Examiner F. E. WADDELL, Assistant Examiner US. Cl. X.R. 

